tbuckley/cabot-search huggingface dataset:
Abstract P1075: Igf-1 Signaling And Nuclear Localization Of Pdgfralpha Tyrosine Kinase Activity Control The Fibrotic Response Of Mesenchymal Stromal Cells To Myocardial Ischemia
Authors: Maria Paola P Santini, Kiyotake Ishikawa, Evren U Azeloglu
Journal: Circulation Research (2023)

Background and Hypothesis: The role of mesenchymal stromal cells expressing the platelet-derived growth factor alpha (PDGFRα + MSCs) has been associated with fibro-adipogenic pathologies. Based on our previous data in regenerating skeletal muscle and the data herein described, we hypothesized that specific and distinct mesenchymal stromal cells exist in the heart, which will retain regenerative capacities by modulating the spatiotemporal distribution of the PDGFRα tyrosine kinase activity and the re-expression of specific regenerative molecules. Methods: Myocardial ischemia/reperfusion (I/R) was induced in mice with standard procedures and in compliance with the regulations of the NIH and the local institutional animal care. Results: Confocal imaging and immunophenotyping analyses showed that cardiac PDGFRα + MSCs exist as two distinct sub-populations expressing markers of specialized and differentiated cells, such as endothelial (60.3%±7.9% expressing CD31) and cardiomyocyte cell-cell anchoring markers (89%± 0.6% of population expressing desmocollin 2/3), while also retaining the expression of mesenchymal markers. Importantly, whereas PDGFRα + MSCs organized in vessel-like structures expressing CD31 during the acute phase after I/R, they transitioned into myofibroblast-like cells in ischemic subacute conditions. Identifying the mechanisms regulating PDGFRα + MSCs dual function remains a critical roadblock. In addressing this gap, we discovered that the transition to myofibroblast-like cells was associated to nuclear shuttling of PDGFRα C-terminal tyrosine kinase domain and ligand-dependent increased nuclear area, suggesting receptor-mediated activation of chromatin remodeling. Furthermore, we discovered that therapeutic re-expression of downregulated paracrine factors, such as the IGF-1Ea splice variant, correlated with long-term organization of PDGFRα + /CD31 + in small capillaries, overcoming the late ischemic transition to fibrotic cells. Conclusions: Taken together, these data suggest that by modulating PDGFRα intracellular shuttling or altering the expression of regenerating genes, may therapeutically direct PDGFRα + MSCs duality to reduce fibrosis, while harnessing their beneficial properties.
Abstract P3102: Sex Differences In Outcomes Among Heart Failure Hospitalizations
Authors: Sandeep Appunni, Muni Rubens, Anshul Saxena, Venkataraghavan Ramamoorthy, Mukesh Roy, Md Ashfaq Ahmed, Zhenwei Zhang, Yanjia Zhang
Journal: Circulation Research (2023)

Background: Both men and women have a comparable overall lifetime chance of developing heart failure, but there are clear sex differences in the nature of this condition that are both significant and yet underexplored. In this study, we investigate gender differences in clinical characteristics and in-hospital outcomes of heart failure hospitalizations using a large national database. Methods: This study is a retrospective analysis of National Inpatient Sample data, 2016-2019. Hospitalizations ≥41 years of age, admitted for heart failure were included in the study and stratified by sex. The outcomes of the study were in-hospital mortality rate, prolonged hospital length of stay, mechanical ventilation, mechanical circulatory support, vasopressors use, and adverse disposition. Propensity score matching with conditional logistic regression analysis was done to compare outcomes between males and females. Results: A total of 4,704,684 primary heart failure hospitalizations were included for the analysis. Of these 2,447,784 (52.0%) were males and 2,256,899 (48.0%) were females. In-hospital mortality ( P &lt;0.001), mechanical ventilation ( P &lt;0.001), mechanical circulatory support ( P &lt;0.001), and vasopressors use ( P &lt;0.001) were significantly lower among females, while prolonged length of stay ( P &lt;0.001) and disposition other than home ( P &lt;0.001) were higher among females. Conditional logistics regression analysis showed that females had significantly lower odds for mortality (aOR, 0.92, 95% CI: 0.89-0.94), mechanical ventilation (aOR, 0.89, 95% CI: 0.86-0.92), mechanical circulatory support (aOR, 0.54, 95% CI: 0.50-0.58), vasopressor use (aOR, 0.70, 95% CI: 0.66-0.74), and significantly higher odds for prolonged length of stay (aOR, 1.05, 95% CI: 1.04-1.06) and disposition other than home (aOR, 1.32, 95% CI: 1.31-1.34) Conclusion: Results of our study show that there are significant differences in outcomes between males and females hospitalized for heart failure. Further research is required to delineate how sex affects several aspects of heart failure, including epidemiology, risk factors, pathogenesis, response to medication, and eventually outcomes.
Abstract P1160: Genome-wide CRISPR Screen Reveals Genetic And Small Molecule Modifiers Of Ca <sup>2+</sup> -mediated Cell Death
Authors: Oscar Reyes Gaido, Jonathan Granger, Kate Schole, Elizabeth D Luczak
Journal: Circulation Research (2023)

Ca 2+ is a ubiquitous and highly regulated signaling ion in living cells. Thus, Ca 2+ is typically maintained at a low intracellular concentration (10-100 nM), tens of thousands of times lower than the outside space (1-2 mM). Failure to maintain this homeostasis—due to membrane instability or energetic failure—allows supraphysiologic concentrations to enter cells and trigger cell death pathways including mitochondrial permeability transition, apoptosis, and autophagy. This mechanism of cell death is shared by many conditions including myocardial infarction, stroke, and sepsis. Targeting of known protein effectors downstream of Ca 2+ overload, such as caspases and calpains, has not yet translated into therapies due to specificity concerns. Therefore, there is still a pressing need for a comprehensive examination of genetic effectors involved in Ca 2+ -induced cell death. Here, we performed genome-wide CRISPR knockout screening in human cells and identified genes and pathways previously unknown to mediate cell toxicity after Ca 2+ overload. We reveal 115 gene knockouts that protected cells and 9 knockouts that sensitized cells to intracellular Ca 2+ . Notably, genetic ablation of members from the store operated calcium entry, very long-chain fatty acid synthesis, and SWItch/Sucrose Non-Fermentable (SWI/SNF) pathways provided marked protection. Reassuringly, genes known to maintain Ca 2+ homeostasis (e.g., STIM1, ATP2B4, ATP2B1) were recovered by the screen. By comparing against the essential and druggable genomes, we determined that 82 of the protective knockouts are non-essential genes and 21 are targetable with small molecules. Therefore, a significant portion of our hits represent viable but unexplored targets for conditions that feature Ca 2+ overload. We tested this hypothesis using small molecule blockade of hits overlapping with the druggable genome. We found several antagonists that resulted in a reduction of ionomycin-induced cell death. Altogether, our results reveal numerous novel effectors of Ca 2+ -mediated cell death that will serve as a basis for improved mechanistic understanding of cell death and as targets for pharmacotherapeutic design.
Abstract P3101: Dietary Nitrates Negate Beneficial Cardiac Adaptations To Aerobic Exercise In A Sex-specific Manner
Authors: Elise S Bisset, Susan E Howlett
Journal: Circulation Research (2023)

Dietary supplements such as nitrates are commonly combined with aerobic exercise with the idea that this will improve performance and cardiac function. Whether this combination leads to beneficial effects on cardiac function at the cellular level is unclear, and few studies have used females. We determined whether dietary nitrates and/or aerobic exercise improves fitness and cardiovascular health in adult mice (both sexes) and explored underlying mechanisms. C57Bl/6 mice (9-mos) were given 1mM sodium nitrate (drinking water) and/or access to a running wheel for 3 mos. Cardiac function (echocardiography), blood pressure (tail cuff) and fitness (treadmill) were measured in mice at endpoint; calcium transients (Fura-2) and calcium currents were measured in isolated ventricular myocytes at endpoint. Exercised mice had better fitness and improved cardiac function when compared to sedentary mice, regardless of sex. Nitrates had no effect on blood pressure, total voluntary wheel running, or endpoint fitness measured as distance to exhaustion (242 ± 28 vs 294 ± 37 m, p=0.29; 122 ± 29 vs 136 ± 16 m, p=0.69 in females and males, respectively) compared to exercised controls. However, nitrates combined with exercise impaired cardiac function in a sex-specific manner. Nitrate-treated male mice who exercised had lower E/A ratios (1.8 ± 0.3 vs 1.3 ± 0.1, p=0.01) and thus worse diastolic function than control exercised male mice. By contrast, nitrate-treated female mice who exercised had smaller global longitudinal strain (-19.5 ± 1.5 vs -11.8 ± 3.0%, p=0.01) than control exercised mice, indicative of worse systolic function. Corresponding changes were seen at the cellular level. Male mice given nitrates had slower times to 50% calcium transient decay than controls (44.8 ± 4 vs 73.8 ± 6 ms, p=0.01), while females given nitrates had slower velocity to peak calcium (0.031 ± 0.004 vs 0.018 ± 0.003 μm/ms, p=0.005). These changes in calcium transients were attributable, at least in part, to corresponding changes in calcium currents. Thus, exercise improves fitness regardless of nitrates and promotes beneficial cardiac adaptations in systolic and diastolic function, but these benefits are negated when exercise is combined with dietary nitrates in a sex-specific fashion.
Abstract P2046: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy
Authors: Chun Chou, Gregory Martin, Gayani Perera, Junya Awata, Robert M Blanton, Xuehong Cao, Audrey Tripp, Tina Phan, Abdullah Alissa, Mossab Aljuaid, Christopher Madias, Munther Homoud, Jonas B Galper, Michael T Chin
Journal: Circulation Research (2023)

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation. While mutations in sarcomere genes can account for a substantial proportion of familial cases, 40-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of homozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased maximal elastance, reduced diastolic function and are more susceptible to ventricular tachycardia with programmed stimulation. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Studies on isolated adult cardiomyocytes reveal altered fractional shortening, calcium dyshomeostasis, prolonged action potential duration, and T-wave alternans. Crossing of CRYAB R123W mice with a mybpc3 knock-in model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in this model are independent of the sarcomere. Thus, our data establish the Cryab R123W allele as a novel genetic model of HCM that potentially unveils additional sarcomere-independent mechanisms of cardiac pathological hypertrophy and sudden cardiac death.
Abstract P2013: Cardiac Remodeling, Amyloidosis, Neurotrophic Signaling, And Innervation Impairment In The Tg2576 Model Of Alzheimer's Disease
Authors: Andrea Elia, Rebecca Parodi-Rullan, Rafael Vazquez-Torres, Ashley Carey, Silvia Fossati
Journal: Circulation Research (2023)

Background: In Alzheimer's disease (AD), the characteristic cerebral amyloid β (Aβ) deposition and tau pathology are accompanied by a progressive loss of the two main neuromodulators, NGF and BDNF. This AD-mediated derangement of the brain's neuro-signaling pathway may extend to the periphery and, along with potential peripheral amyloid deposition, induce peripheral nervous system impairment, thus affecting other organs, including the heart. However, whether and how AD pathology affects cardiac physiology, neurotrophins, innervation, and heart amyloidosis is still unclear. Method: Here, we describe for the first time that cardiac remodeling and neuro-signaling dysregulation are present in the hearts of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Results: Echocardiographic analysis showed significant deterioration of left ventricle function, as demonstrated by a decline of both ejection fraction and fraction shortening in 12-month-old Tg2576 mice compared to age-matched WT littermates. The transgenic mice hearts displayed an increase in interstitial fibrosis, with an accumulation of amyloid aggregates, including Aβ, associated with severe cardiac nervous system dysfunction. Tg2576 mice exhibited a depletion in cardiac nerve fiber density, both adrenergic (stained with tyrosine hydroxylase- TH) and regenerating nerve terminals (labeled with GAP-43), compared to the WT mice. This myocardial denervation was accompanied by a decline in NGF and BDNF protein expression as well as GAP-43 expression in both the brain and heart of Tg2576 mice. Likewise, human neuroblastoma cells (SH-SY5Y) and human cardiomyocytes (AC16) challenged with human Aβ-40 or, Aβ-42 oligomers showed significant downregulation of both BDNF and GAP-43 activity. Conclusion: Overall, this study highlights the harmful impact of cerebral amyloidosis on the cardiac nervous system and heart physiology, providing potential therapeutic targets, such as neurotrophic factors, to prevent or limit AD-mediated degenerative mechanisms in the cardiovascular system.
Abstract P2147: Inhibition Of Cdk7 Attenuates Doxorubicin Cardiotoxicity And Enhances Anticancer Efficacy
Authors: Jingrui Chen, Jing Wei, Peng Xia, Yuening Liu, Zhaokang Cheng
Journal: Circulation Research (2023)

Background: The anthracycline family of anticancer agents such as doxorubicin (DOX) can induce apoptotic death of cardiomyocytes and cause cardiotoxicity. We previously reported that DOX-induced apoptosis is accompanied by cardiomyocyte cell cycle-reentry. Cell cycle progression requires cyclin-dependent kinase 7 (CDK7)-mediated activation of downstream cell cycle CDKs. This study aims to determine whether CDK7 can be targeted for cardioprotection during anthracycline chemotherapy. Methods and Results: DOX exposure induced CDK7 activation in mouse heart and isolated cardiomyocytes. Cardiac-specific ablation of Cdk7 attenuated DOX-induced cardiac dysfunction and fibrosis. Treatment with the covalent CDK7 inhibitor THZ1 also protected against DOX-induced cardiomyopathy and apoptosis. DOX induced activation of the proapoptotic CDK2-FOXO1-Bim axis in a CDK7-dependent manner. In response to DOX, endogenous CDK7 directly bound and phosphorylated CDK2 at Thr160 in cardiomyocytes, leading to full CDK2 kinase activation. Importantly, inhibition of CDK7 further suppressed tumor growth when used together with DOX in an immunocompetent mouse model of breast cancer. Conclusions: Activation of CDK7 is necessary for DOX-induced cardiomyocyte apoptosis and cardiomyopathy. Our findings uncover a novel proapoptotic role for CDK7 in cardiomyocytes. Moreover, this study suggests that inhibition of CDK7 attenuates DOX-induced cardiotoxicity, but augments the anticancer efficacy of DOX. Therefore, combined administration of CDK7 inhibitor and DOX may exhibit diminished cardiotoxicity but superior anticancer activity.
Abstract P2010: Relationship between echocardiographic parameters and invasively measured left ventricular filling pressure in the persistent atrial fibrillation with preserved left ventricular systolic function
Authors: JIHUN AHN
Journal: Circulation Research (2023)

Background: Among patients with normal systolic function, elevated left ventricular end diastolic pressure (LVEDP) could represent early diastolic dysfunction or could be the main physiological consequence of diastolic dysfunction. However, the evaluation of LVEDP using classic echocardiographic assessment has been challenging in the setting of atrial fibrillation (AF). The aim of this study was to investigate the methods for predicting LVEPD in patients with persistent AF. Methods: Clinical data, laboratory data, and echocardiography findings were assessed in 90 patients with chronic AF who were undergoing diagnostic left-heart catheterization. LVEDP and standard echocardiographic measurements including pulmonary arterial systolic pressure (PASP) were evaluated. Results: E/e’ (r=0.448, p&lt;0.001), E/Vp (r=0.471, p&lt;0.001) and PASP (r=0.421, p&lt;0.001) correlated well with LVEDP (figure 1). Using receiver operating characteristic analysis, the optimal cut-off for E/e’ was 13 (sensitivity, 88%; specificity, 65%) to predict LVEDP of &gt;15 mmHg (figure ). Conclusion: E/e’, E/Vp and PASP were well correlated with LVEDP in patients with AF with preserved EF. E/e’ greater than 13 may suggest elevated LVEDP (&gt;15 mmHg) in patients with persistent AF.
Abstract P1045: Replacement Of Wearable-device-measured Sedentary Time By Physical Activity, Genetic Susceptibility, And Risk Of Coronary Heart Disease
Authors: Youngwon Kim, Haeyoon Jang, Mengyao Wang, Tessa Strain, Stephen J Sharp, Qiaoxin Shi, Shiu Lun Au Yeung, Shan Luo, Simon Griffin, Nicholas J Wareham, Soren Brage
Journal: Circulation Research (2023)

Backgrounds: Excess sedentary time (ST) is recognized as an important modifiable risk factor for coronary heart disease (CHD). However, whether the associations of genetic susceptibility with CHD incidence can be modified by replacing wearable-device-measured ST with physical activity (PA) is unknown. This study aims to examine the combined associations of genetic susceptibility to CHD, and wearable-device-measured ST replaced by moderate-to-vigorous PA (MVPA) or light PA in relation to incident CHD. Methods and Findings: This study included 75,545 white British (57% female) with valid wrist-worn accelerometer data and without prevalent CHD/stroke from UK Biobank. Genetic susceptibility to CHD was quantified through weighted polygenic risk scores for CHD based on 300 single-nucleotide polymorphisms. Wrist-worn accelerometer data were used to derive ST, light PA and MVPA. The hazard ratio of CHD was 1.36 (95% CI: 1.03-1.80) for every-30-minute/day-increase in ST relative to other movement behaviors, after adjusting for genetic risk and confounders. Reallocation of any amount of ST (as little as 1 minute/day) into the same MVPA time (but not light PA) was associated with lower CHD hazards overall and within strata of genetic risk: no evidence of interaction between genetic risk and ST (p-value: 0.739). However, differences in absolute risk of CHD for ST replaced by MVPA were greater at high genetic risk versus low genetic risk. Limitations of our study include no causal evidence derived, limited generalizability to individuals of other ethnic groups or with sub-clinical symptoms, and potential residual confounding. Conclusions: Replacing any amount of ST with an equal amount of MVPA time is associated with a lower relative risk of developing CHD at all levels of genetic susceptibility to CHD. Potential reductions in absolute risk of CHD through replacement of ST by MVPA in equivalent amounts may be greater in individuals at high genetic risk of CHD.
Abstract P2131: Sialidase Neu3: A Novel Cardioprotective Target Against Ischemia And Reperfusion Injury
Authors: Marco Piccoli, Simona Coviello, Ivana Lavota, Andrea Ghiroldi, Federica Cirillo, Carlo Pappone, Luigi Anastasia
Journal: Circulation Research (2023)

Coronary reperfusion techniques are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction. However, they also lead to what is known as ischemia and reperfusion injury (IRI), which causes additional damage and heart failure. Despite the urgent need for cardioprotective strategies against IRI, none has yet been introduced into clinical practice, suggesting that a more detailed characterization of the molecular mechanisms underlying the pathogenesis of IRI is essential. In this regard, our research group has shown that sialidase Neu3, an enzyme responsible for removing sialic acid from glycosphingolipids, is modulated during IRI in vivo and that its constitutive overexpression in rat cardiomyoblasts is sufficient to counteract the deleterious effects of IRI through activation of reperfusion injury salvage kinase (RISK) and the HIF-1α pathway. Thus, in this study, we developed an inducible model of Neu3 overexpression in human cardiac cells (AC16) and in mice to further elucidate the role of this protein in promoting cardioprotection. Inducible upregulation of Neu3 significantly increased cell resistance and reduced oxidative stress in AC16 exposed to IRI in vitro. These beneficial effects were related to Neu3-mediated maintenance of mitochondrial membrane potential, which was altered in control cells. Moreover, RNAseq data showed that Neu3 activation was associated with upregulation of the cellular responses to stress, whereas, in contrast, the pro-inflammatory signaling pathways of TNF-α and IL-22 were downregulated. We also generated αMHC-Cre/LSL-Neu3 mice for the first time by crossing the tamoxifen-inducible αMHC-Cre mouse with a mouse carrying a floxed-transcriptional STOP sequence upstream of Neu3. These mice were characterized for cardiac morphology and functionality and showed no significant differences compared with wild-type mice. They will undergo surgical induction of IRI to test the beneficial effects of Neu3. Based on our findings, it can be hypothesized that Neu3 plays a significant role in the cardiac response to IRI. Consequently, targeting Neu3 may hold therapeutic promise in increasing cardioprotection and mitigating the incidence and severity of myocardial infarction.